OBJECTIVE: There is controversy as to whether hypothyroidism increases cardiovascular risk. The effect of levothyroxine on the cardiovascular risk profile is also unclear. Recent studies suggest that there is evidence of inflammation and endothelial dysfunction in hypothyroidism. Soluble CD40 ligand (sCD40L) is a protein expressed mainly by activated platelets which have been found to be associated with cardiovascular events. The aim of our study was to investigate serum sCD40L levels and the effect of levothyroxine replacement on sCD40L levels in overt and subclinical hypothyroidism. DESIGN: We assessed lipid profile, serum sCD40L and hsCRP levels in 21 overt and 22 subclinical hypothyroid age-matched female patients with chronic autoimmune thyroiditis at baseline and one month after achieving euthyroidism by levothyroxine replacement, and compared them with the data from 22, age-matched, healthy controls. RESULTS: Overt and subclinical hypothyroid patients had decreased sCD40L levels compared to age-matched controls. The patients with subclinical hypothyroidism had slightly increased hsCRP levels, but the result was not statistically significant. In multiple regression analysis, FT3 and FT4 were found to be independent predictors of sCD40L levels. After levothyroxine replacement, serum sCD40L levels increased significantly in the patients with overt hypothyroidism. Although an increase was also observed in the subclinical hypothyroid group, it was not statistically significant. Levothyroxine replacement had no significant effect on hsCRP levels in the patients with overt hypothyroidism. However, the subjects with subclinical hypothyroidism showed a significant reduction in hsCRP levels after levothyroxine. CONCLUSION: The values of sCD40L and hsCRP in our study suggest that inflammatory pathways are complex and may be affected by different factors in hypothyroidism.